Nu-phenethyl-beta-alanine derivatives



?1crystallization purification:

Patented Apr. 11, 1950 ()FFICEI N -PHENETHYL-BETA-LALAN1NE I DE I A E N9 'Iirawiiig App t n" unezzirlarz;

"The present application isf acqnti'nuation-j-in of our cO-pending applicationSeriallium;

194s "and both 'n'ow'abanjdoned.

Our invention relates to certain 'N-phenethyl-beta-alanine derivatives and is" based on the discovery that certain gN-phenethyl beta alanine esters and allrylolamides "have valuable physiological properties;especially in stimulating uterine smooth ,muscle without --acting as; general pfi'essor drugs, combined with low toxicities.

One group of compounds of this type {showing considerable potenci'es are the -compb lv ds in which the phenyl ring'is connected toitheni-tro gen by a pure hydrocarbon chain, and the phenyl ring bears two ethereal oxygen substituents, such as *two-"n'i'ethoxy groups-or a methylene l dioxy group,- these substances"forniing -the subject matter of our simultaneously filed companion application Serial No. 756,336 filed June 21, 1947.

Another group of active substances consists ofgthe N-phenethyl -beta-alanine esters in which the beta-carbon of the phenethyl group (countingirom the nitrogen atom) is Substituted .with

hydroxyl, with or Iwithout'methyl or alkoxy substituents in the phenylrmg. v

These compounds which form the-sub ect n'iattr' of the presentinventionimay' be represented "by the general forinulai IIU $113 cH-'oi1--N c11,crr5"-o'-om niiqwhiretire11sinn mbergen le- 2mm:arrestin ofhydfo'gen' a'n'd methyl; RF is a straight 'chain ;alkyl containing from 1 to 5 carbon atoms and R .ahdi R are' members of the "group "consisting? of i'iydrogen, methyl, methoiz 'y and iethoxy.

Theconipoundsaccording:-to the iinvention as represented in the general formula above, are

tei'tiai'yamines-which -ma be combined -=with vci'ious a'cids to "form salts for convenience ir-'1 handling and stability." 'The'natu'reof the=acids forming these acid saltsof the tertiary amines is ordinarily of noiniportance'ffor .the physiologi- =properties but may influenoe i' the :ease 1 of busin most cases salts of hydrochloric acid are-at least-as .lsatisfacto y as s t of ot er b i ds but so compounds have .been isolated more readily as sulieltes, ph sphates, tart ates; 1 ma t s, vsu

' drobromides,",ete. Su -variations-in animated a the "mannmation i 0rsaniciba esr ts-" em ni v ns hwi ena sist-ph vious; and 'we neithefconsider anypart of jour invention toconsist therein 'nordo we conceive that, any absencelof mention of the use 'ofsuch common acids shall be held to limit the "inveri tion. The'claimsappended hereto are intended to cover the tertiary bases as well as their acid salts:

is .reacted with a "beta-halogeno; usually a -betabromopropioniciester. This reaction is not unsatisfactory but since a separation of basic substances-isnecessary-and since only half (at most) of the m'ore valuableintermediate can be utilized we prefer a second line of synthesis;

According tothissecond method the amine is treated with -an excess-of an ester of acrylic-acid, usually methyl acrylate, the reaction being-in the sense or the equationz- The product so obtained is a tertiary base bases-so ob ain ca ib con te axicabs-desir d s lt b methods generally n n in e an. The nature of the acid-employed isor dinarily of minor importancefor the physiological action but certain salts have physicalproperties making them more or less advantageous for puriiicat qn- .In. m s casesthe or de hav been used and th ar 1 gen all ef r ed butetber salts, such as the bromides; iodidejs 'l phosphates,

In the first of these, the appropriate sulfates, oxalates, tartrates, succinates, malates, etc., have at times proved convenient.

The amines used in the preparation of the compounds according to the invention are well known in the art and their preparation does not form any part of the present invention.

Although other esters of acrylic acid than the methyl ester may be used in the second line of synthesis, methyl acrylate is the most readily available and has generally been employed. The conversion of the beta-alanine methyl esters into higher alkyl esters (corresponding to variations in R can be accomplished conveniently by heating the methyl ester in a large excess of the appropriate higher alcohol containing anhydrous hydrogen chloride under a fractionating .column. During several hours heating, distillate is allowed to pass over gradually and an ester exchange takes place in the solution, the alkyl group of the higher alcohol replacing the methyl group in the ester.

The following list of compounds prepared according to the invention is given by way of illustration, but is not intended as a limitation except as expressed in the claims:

1. N-methyl-N -(beta-hydroxy-beta-4-methylphenylethyl) beta-alanine methyl ester acid malate.

2. N methyl N -(beta-hydroxy beta-2,5-dimethylphenylethyl) beta-alanine methyl ester hydriodide. I

3. N-methyl N -(beta hydroxybeta-2,5-dimethoxyphenylethyl) beta-alanine methyl ester hydrochloride.

4. N-methyl N (beta hydroxy beta-2,5-dimethoxyphenylethyl) beta-alanine ethyl ester hydrochloride.

5. N-methyl N -(beta hydroxy beta-2,5-dimethoxyphenylethyl) beta-alanine n-butyl ester .acid oxalate.

6. N-methyl N (beta hydroxy beta 2,5-di methoxyphenylethyl) beta-alanine n-amyl ester acid oxalate.

'7. N-methyl N beta hydroxy beta-3,4-dimethoxyphenylethyl) beta-alanine methyl ester acid oxalate.

8. l-N-methyl N -(beta-hydroxy-beta-3,4-dimethoxyphenylethyl) beta-alanine methyl ester acid oxalate.

9. N-me'thyl N (beta hydroxy beta-3,4-dlmethoxyphenylethyl) beta alanine ethyl ester hydrobromide. I I

' 10. N-methyl N -(beta hydroxy-beta-2,5-diethoxyphenyl-ethyl) beta-alanine methyl ester hydrochloride.

11. N-methyl N (beta-hydroxy-beta-phenylisopropyl) beta-alanine methyl ester hydrochloride. I

12. N-methyl N -(beta-hydroxy-beta-phenylisopropyl) beta-alanine ethyl ester hydrochloride.

13. 1-N-methyl N (beta-hydroxy-beta-phenylisopropyl) beta-alanine ethyl ester hydrochloride.

14. N-methyl-N-(beta hydroxy-beta-Z-methoxy 5 methylphenylisopropyl) beta alanine methyl ester hydrochloride. I

' 15. N-methyl-N -(beta hydroxy beta-3,4 di- 'methoxyphenylisopropyl) beta alanine methyl ester hydrochloride.

16. d-N-methyl N -(beta hydroxy beta-3,4- dimethoxyphenylisopropyl) beta-alanine methyl ester hydrobromide. 1'7. N-methyl N -(beta hydroxy-beta-3A-dimethoxyphenylisopropyl) beta-alanine ethyl ester hydrochloride.

EXAMPLE 1 N-methyl-N-(beta-hydroacy-beta-2,5-dimethozyphenylethyl) beta-alanine ethyl ester hydrochloride Seventeen g. of beta-hydroxy-beta -(2,5-dimethoxy-phenyl)-ethylmethylamine hydrochloride (for preparation see Baltzly and Buck, J. Am. Chem. Soc. 62, 164 (1940)) was dissolved in water. The solution was basified and the liberated base i was taken into benzene and dried over potassium carbonate. The solution in about 200 cc. of benzene was allowed to stand sixty-four hours with 45 g. -of methyl acrylate and was then warmed on the steam-bath one-half hour. The solution was cooled and poured into acetone to which had been added 10 g. of a solutionof hydrogen chloride in methanol (39% by weight).. Absolute ether was added until the solution was not quite turbid. There crystallized 21 g. of the hydrochloride of Y N-methyl N -(beta-hydroxybeta 2,5 dimethoxyphenylethyl) beta-alanine methyl ester melting at 1545-155" .0. A recrystallization from methanol-acetone-ether mixture raised the melting point to 156-1565 C.,. the product then weighing 20.5 g. y

EXAMPLE 2 N -methyl-N (beta-hydrosry-beta -Zfi -dimethoa:yphenylethyl) beta-alanine ethyl ester hydro chloride Three g. of the corresponding methyl ester obtained according to Example 1 was dissolved in cc. of absolute ethanol to which was added lllg of 35% (by weight) ethanolic hydrogen chloride. The solution was refluxed four hours under a fractionating columnpermitting slow distillation. The solution was then evaporated nearly to dryness, diluted with ethyl acetate and ether and cooled. Colorless needles separated which melted at -6" C. Further crystallization did not raise the melting point and the analysis was correct for the ethyl ester hydrochloride.

EXAMPLE 3 N methyZ- N- (beta-hydromy-b6ta:2,5 -dimethomyphenylethyl) beta-alanine n-butyl ester acid oxalate 'Five g. of the corresponding methyl ester obtained according to Example l-was refluxed in n-butyl alcohol containing dissolved hydrogen chloride by the method of Example 2. The resulting n-butyl ester hydrochloride did not crystallize readily and the product was most-readily purified as the acid oxalate.

EXAMPLE 4 N -methyZ-N (beta-hydroxy-beta-3,4-dimethomyphenylethyl) beta-alanine methyl ester acid oxalate t-it Fifteen g. of beta-hydroxy beta-(3,4-dimetlioxyphenyl) ethylmethylamine (B. P., 152: at 1 mm.) was reacted by the method of Example 1 with 50 g. of methyl acrylate' The hydrochloride proved not to be readily crystallized and the product was transformed to'the acid "oxalate which crystallized from aqueous acetone-ether mixtures forming flattish prisms, M. P., 127- 128 C.

EXAMPLE 5 N methyl N (beta hydroxy beta phenylisopr-opyl) beta-alanine methyl ester hydrochloride EXAMPLE 6 N methyl N (beta hydromy beta. phenylisopropyl) beta-alanine ethyl ester hydrochloride Fifteen g. of d-l ephedrine hydrochloride was dissolved in water. The solution was basified and the ephedrine base was extracted with ether, the extract being dried over potassium carbonate. The ether was evaporated and to the residue (10.2 g.) was added 11.2 g. of ethyl beta-bromopropionate dissolved in 30 cc. of absolute ethanol. The solution was refluxed six hours and the ethanol was evaporated. The residue was dissolved in dilute hydrochloric acid, cooled and treated with a solution of 6 g. of sodium nitrite. The resulting nitroso derivative of the previously unreacted ephedrine was removed by extraction with ether and discarded. The aqueous layer was made strongly alkaline, extracted with ether and the ethereal extracts were dried over potassium carbonate. The ethereal solution was filtered from the desiccant and poured into an excess of hydrogen chloride dissolved in absolute alcohol, The hydrochloride of N-methyl-N-(beta-hydroxy-beta-phenylisopropy1) beta-alanine ethyl ester crystallized immediately.

EXAMPLE '7 1 -N-methyl-N- (be-ta-hydroxy-beta-phenylisopropyl) beta aldnine ethyl ester hydrochloride By the method of Example 6, l-ephedrine was reacted with ethyl acrylate to yield the desired product.

EXAMPLE 8 N methyl N (beta hydroxy beta 2 methoxy-5-methylphenyl isopropyl) beta-alanine methyl ester hydrochloride Five g. of beta-(2-methoxy-5-methylphenyl)- beta-hydroxy isopropyl methylamine hydrochloride (for preparation see Ardis, Baltzly and Schoen, J. Am. Chem. $00.68, 591 (1946)) was dissolved in water. The base Was liberated and treated with 5.1 g. of methyl acrylate according to the method of Example 1. The product, obtained in 84% yield, was crystallized from methanol-acetone-ether mixtures and melted at 179-180 C.

We claim:

1. A new composition of matter selected from the group consisting of the compounds having the following general formula:

in which R in a member of the group consisting of hydrogen and methyl, R is a straight chain alkyl Containing from 1 to 5 carbon atoms and R and R are members of the group consisting of hydrogen, methyl, methoxy and ethoxy, and the salts thereof.

2. A new composition of matter selected from the group consisting of the compounds having I the following general formula R3 OH CH3 in which R is a straight chain alkyl containing from 1 to 5 carbon atoms, and the salts thereof.

4. N methyl N (beta hydroxy beta 2,5- dimethoxyp-henylethyl)beta-alanine methyl ester hydrochloride.

5. N methy N (beta hydroxy beta 3,4- dimethoxyphenylethyl) beta-alanine methyl ester acid oxalate.

RICHARD BALTZLY. ARTHUR P. PHILLIPS. LOWELL O. RANDALL.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Peyer Jan. 21, 1941 OTHER REFERENCES J. R. Thayer et a1., Chem. Abst, vol. 22, page 81 (1928).

Number 

1. A NEW COMPOSITION OF MATTER SELECTED FROM THE GROUP CONSISTING OF THE COMPOUNDS HAVING THE FOLLOWING GENERAL FORMULA: 